Genital abnormalities in Pallister–Hall syndrome: Report of two patients and review of the literature

Abstract

We describe two patients with Pallister-Hall syndrome (PHS) with genital abnormalities: a female with hydrometrocolpos secondary to vaginal atresia and a male with micropenis, hypoplastic scrotum, and bilateral cryptorchidism. Nonsense mutations in GLI3 were identified in both patients. Clinical and molecular findings of 12 previously reported patients who had GLI3 mutations and genital abnormalities were reviewed. Genital features in the male patients included hypospadias, micropenis, and bifid or hypoplastic scrotum, whereas all the females had hydrometrocolpos and/or vaginal atresia. No hotspot for GLI3 mutations has been found. The urogenital and anorectal abnormalities associated with PHS might be related to dysregulation of SHH signaling caused by GLI3 mutations rather than hormonal aberrations. We recommend that clinical investigations of genital abnormalities are considered in patients with PHS, even those without hypopituitarism.

Hedgehog signaling pathway: Epigenetic regulation and role in disease and cancer development

“…Pallister–Hall syndrome is another rare genetic disorder caused by nonsense, frameshift, and single splice mutations in the middle third of GLI3, which includes exons 13, 14, and part of 15, leading to the production of an abnormally short version of the GLI3 protein. Unlike the normal GLI3 protein, which can turn target genes on or off, the short protein can only turn off (repress) target genes (Narumi et al, ). Patients may have a spectrum of anomalies including polydactyly, syndactyly, hypothalamic hamartoma (abnormal growth in the brain), pituitary insufficiency, and may die as neonates from undiagnosed and untreated adrenal insufficiency (Biesecker, ).…”

Clinical Syndromes and Associations with Persistent Pulmonary Hypertension of the Newborn

“…The disorder is transmitted in an autosomal dominant inheritance pattern and so a family history is critical. Mutations of GLI3 on 7p13 is responsible for this disorder (Narumi et al, 2010).…”

A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies

“…Classic GCPS is characterized by the triad of widely spaced eyes, macrocephaly, and PPD‐IV or mixed pre‐ and postaxial polysyndactyly in at least one limb (Balk & Biesecker, ; Johnston et al, ). PHS is described as an association of mesoaxial or PAP‐A/B with hypothalamic hamartoma, though patients can also present with some combination of bifid epiglottis, non‐digit skeletal defects, anorectal or genitourinary malformations, and sensorineural hearing loss (SNHL) (Hall et al, ; Johnston et al, ; Narumi et al, ). Mild forms of GCPS and PHS can also be incorrectly diagnosed as isolated polydactyly and syndactyly.…”